title: Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis.
abstract: BACKGROUND
  On the basis of various clinical and MRI measurements, the phase 3 Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) study in patients with relapsing-remitting multiple sclerosis (RRMS) showed that short-course oral treatment with cladribine at cumulative doses of 3·5 and 5·25 mg/kg over 96 weeks was more effective than placebo. Achieving sustained freedom from disease activity is becoming a viable treatment goal in RRMS; we therefore aimed to assess the effects of cladribine on this composite outcome measure by doing a post-hoc analysis of data from the CLARITY study.
  
  
  METHODS
  Freedom from disease activity is composed of three components that are commonly used individually as endpoints in clinical trials; it is defined as the patient having no relapse, no 3-month sustained change in expanded disability status scale (EDSS) score, and no new MRI lesions (no T1 gadolinium-enhancing or active T2 lesions) over a specified period. We assessed the effect of two doses of cladribine tablets versus placebo on the proportion of patients who were free from disease activity based on the individual components, all pair-wise combinations, and the composite of the three components (freedom from disease activity). Freedom from disease activity was analysed at 24, 48, and 96 weeks, and in subgroups of patients stratified according to baseline demographic and disease characteristics (age, disease duration, previous treatment with disease-modifying therapy, T1 gadolinium-enhancing lesion number, T2 lesion volume, EDSS score, number of previous relapses, and highly active disease).
  
  
  RESULTS
  Of the 1326 patients randomly assigned to treatment in the CLARITY study, 1192 were assessable for freedom from disease activity at 96 weeks. Over 24 weeks, 266 (67%) of 395 patients in the cladribine 3·5 mg/kg group and 283 (70%) of 406 in the cladribine 5·25 mg/kg group were free from disease activity, versus 145 (39%) of 373 in the placebo group (odds ratio [OR] 3·31, 95% CI 2·46-4·46 for the 3·5 mg/kg group; and 3·68, 2·73-4·97 for the 5·25 mg/kg group; both p<0·0001). Over 48 weeks, 208 (54%) of 384 patients in the cladribine 3·5 mg/kg group and 222 (56%) of 396 patients in the cladribine 5·25 mg/kg group were free from disease activity, versus 86 (24%) of 360 patients in the placebo group (OR 3·80, 2·77-5·22 for the 3·5 mg/kg group; 4·13, 3·02-5·66 for the 5·25 mg/kg group; both p<0·0001). Over 96 weeks, 178 (44%) of 402 patients in the cladribine 3·5 mg/kg group and 189 (46%) of 411 patients in the cladribine 5·25 mg/kg group were free from disease activity, versus 60 (16%) of 379 patients in the placebo group (OR 4·28, 3·05-6·02 for the 3·5 mg/kg group; 4·62, 3·29-6·48 for the 5·25 mg/kg group; both p<0·0001). The effects of cladribine tablets on freedom from disease activity were significant across all patient subgroups.
  
  
  CONCLUSIONS
  Treatment with cladribine tablets significantly increased the proportion of patients with sustained freedom from disease activity over 96 weeks compared with placebo. Sustained freedom from disease activity could become an important measure of therapeutic response in RRMS.
  
  
  BACKGROUND
  Merck Serono SA-Geneva, Switzerland; an affiliate of Merck, Darmstadt, Germany.
authors.affiliation: Queen Mary University London, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, London, UK. g.giovannoni@qmul.ac.uk
authors.forename: Gavin
authors.initials: G
authors.lastname: Giovannoni
authors.forename: Stuart
authors.initials: S
authors.lastname: Cook
authors.forename: Kottil
authors.initials: K
authors.lastname: Rammohan
authors.forename: Peter
authors.initials: P
authors.lastname: Rieckmann
authors.forename: Per Soelberg
authors.initials: PS
authors.lastname: Sørensen
authors.forename: Patrick
authors.initials: P
authors.lastname: Vermersch
authors.forename: Anthony
authors.initials: A
authors.lastname: Hamlett
authors.forename: Vissia
authors.initials: V
authors.lastname: Viglietta
authors.forename: Steven
authors.initials: S
authors.lastname: Greenberg
mesh_terms: D017338:Cladribine / Q000008:administration & dosage / Q000627:therapeutic use*; D018572:Disease-Free Survival; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy*; D016017:Odds Ratio; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D017338:Cladribine